1. Field of the Invention
The invention generally relates to pathology and physiology in vertebrate species involving cytokines and other cellular signaling mechanisms, and also diagnostic assays involving cytokines and other cellular signaling mechanisms. Other aspects of the invention relate to macrophage migration inhibitory factor (MIF) as a myocardial depressant factor and as a mediator of endotoxin-induced cardiac dysfunction in vivo. Other aspects of the invention relate to mediating and/or inhibiting the production or activity of MIF, and compounds, compositions, methods of treating and preventing cardiac dysfunction, sepsis, burn injury or other conditions related to burns. Other aspects of the invention relate to the MIF release from the heart, liver, and spleen and the role of TNF receptor I/II signaling after LPS challenge. Other aspects of the invention relate to TNF receptor I/II signaling independent release of MIF into the serum. Other aspects of the invention relate to the expression of CD74 on cardiomyocytes and its mediation of cardiac dysfunction.
2. Background of the Technology
Macrophage migration inhibitory factor (MIF) is a pluripotent, pro-inflammatory cytokine whose mechanisms of action have been scrutinized over the past four decades. The current understanding in the art relating to MIF includes studies directed to its crystallization as a trimer, its physiologically relevant oligomerization state; its putative membrane receptor(s); and the physiologic relevance of its intracellular enzymatic activity as a tautomerase and oxidoreductase.
Many studies have demonstrated that MIF has an important role in diseases as diverse as rheumatoid arthritis (M. Leech, et al., “Macrophage Migration Inhibitory Factor in Rheumatoid Arthritis: Evidence of Proinflammatory Function and Regulation by Glucocorticoids”, Arthritis Rheum, 42, 1601-1608 (1999), M. Leech, et al., “Involvement of Macrophage Migration Inhibitory Factor in the Evolution of Rat Adjuvant Arthritis”, Arthritis Rheum., 41, 910-917 (1998), A. Mikulowska, et al., “Macrophage Migration Inhibitory Factor is Involved in the Pathogenesis of Collagen Type 11-Induced Arthritis in Mice”, J. Immunol., 158, 5514-5517 (1997)), delayed-type hypersensitivity (J. Bernhagen, et al., “An Essential Role for Macrophage Migration Inhibitory Factor in the Tuberculin Delayed-Type Hypersensitivity Reaction”, J. Exp. Med., 183, 277-282 (1996), H. Y. Lan, et al., “De Novo Renal Expression of Macrophage Migration Inhibitory Factor During the Development of Rat Crescentic Glomerulonephritis”, Am. J. Pathol., 149, 1119-1127 (1996), H. Y. Lan, et al., “Macrophage Migration Inhibitory Factor Expression in Human Renal Allograft Rejection”, Transplantation, 66, 1465-1471 (1998), H. Y. Lan, et al., “TNF-Alpha Up-Regulates Renal MIF Expression in Rat Crescentic Glomerulonephritis”, Mol. Med., 3, 136-144 (1997), T. Shimizu, et al., “Increased production of Macrophage Migration Inhibitory Factor by PBMCs of Atopic Dermatitis”, J. Allergy Clin. Immunol., 104, 659-669 (1999)), inflammatory lung disease (S. C. Donnelly, et al., “Regulatory Role for Macrophage Migration Inhibitory Factor in Acute Respiratory Distress Syndrome”, Nat. Med., 3, 320-323 (1997), H. Makita, et al., “Effect of Anti-Macrophage Migration Inhibitory Factor Antibody on Lipopolysaccharide-Induced Pulmonary Neutrophil Accumulation”, Am. J. Respir. Crit. Care Med., 158, 573-579 (1998), A. G. Rossi, et al., “Human Circulating Eosinophils Secrete Macrophage Migration Inhibitory Factor (MIF). Potential Role in Asthma”, J. Clin. Invest., 101, 2869-2874 (1998)), cancer (J. Chesney, et al., “An Essential Role for Macrophage Migration Inhibitory Factor (MIF) in Angiogenesis and Growth of a Murine Lymphoma”, Mol. Med., 5, 181-191 (1999), M. T. del Vecchio, et al., “Macrophage Migration Inhibitory Factor in Prostatic Adenocarcinoma: Correlation with Tumor Grading and Combination Endocrine Treatment-Related Changes”, Prostate, 45, 51-57 (2000), J. D. Hudson, et al., “A1 Proinflammatory Cytokine Inhibits p53 Tumor Suppressor Activity”, J. Exp. Med., 190, 1375-1382 (1990), A. Kamimura, et al., “Intracellular Distribution of Macrophage Migration Inhibitory Factor Predicts the Prognosis of Patients with Adenocarcinoma of the Lung”, Cancer, 89, 334-341 (2000), K. Meyer-Siegler, et al., “Increased Stability of Macrophage Migration Inhibitory Factor (MIF) in DU-145 Prostate Cancer Cells”, J. Interferon Cytokine Res., 20, 769-778 (2000), T. Shimizu, et al., “High Expression of Macrophage Migration Inhibitory Factor in Human Melanoma Cells and Its Role in Tumor Cell Growth and Angiogenesis”, Biochem. Biophys. Res. Commun., 264, 751-758 (1999), Takahashi, et al., “Involvement of Macrophage Migration Inhibitory Factor (MIF) in the Mechanism of Tumor Cell Growth”, Mol. Med., 4, 707-714 (1998)), myocardial infarction (M. Takashashi, et al., “Elevation of Plasma Levels of Macrophage Migration Inhibitory Factor in Patients with Acute Myocardial Infarction”, Am. J. Cardiol., 89, 248-249 (2002), M. Takahashi, et al., “Macrophage Migration Inhibitory Factor as a Redox-Sensitive Cytokine in Cardiac Myocytes”, Cardiovasc Res., 52, 438-445 (2001), C. M. Yu, et al., “Elevation of Plasma Level of Macrophage Migration Inhibitory Factor in Patients with Acute Myocardial Infarction”, Am. J. Cardiol., 88, 774-777 (2001)), and septic shock (J. Berhnagen, et al., “MIF is a Pituitary-Derived Cytokine that Potentiates Lethal Endotoxaemia”, Nature, 365, 756-759 (1993), M. Bozza, et al., “Targeted Disruption of Migration Inhibitory Factor Gene Reveals Its Critical Role in Sepsis”, J. Exp. Med. 189, 341-346 (1999), T. Calandra, et al., “MIF as a Glucocorticoid-Induced Modulator of Cytokine Production”, Nature, 377, 68-71 (1995), T. Calandra, et al., “Protection from Septic Shock by Neutralization of Macrophage Migration Inhibitory Factor”, Nat. Med., 6, 164-170 (2000), T. Calandra, et al., “Macrophage Migration Inhibitory Factor is a Critical Mediator of the Activation of Immune Cells by Exotoxins of Gram-Positive Bacteria”, Proc. Natl. Acad. Sci. USA, 95, 11383-11388 (1998)). There is some evidence that monoclonal or polyclonal anti-MIF antibodies may affect the pathology of sepsis, but their role has not been exhaustively characterized in humans. However, during septic shock, MIF is increased in the plasma of animals and humans, and the blockade of MIF activity by monoclonal or polyclonal antibodies results in a marked improvement in the survival of animals with experimentally induced sepsis (M. Bozza, et al., “Targeted Disruption of Migration Inhibitory Factor Gene Reveals Its Critical Role in Sepsis”, J. Exp. Med. 189, 341-346 (1999), T. Calandra, et al., “Protection from Septic Shock by Neutralization of Macrophage Migration Inhibitory Factor”, Nat. Med., 6, 164-170 (2000)).
The blockade of MIF activity has been demonstrated with a number of inhibitors. Blockade of MIF enzymatic activity has been demonstrated with diverse chemical compounds as shown in U.S. patent application Ser. No. 10/226,299, filed Aug. 23, 2002, now pending. See also, for instance, U.S. Pat. No. 6,492,428. Antibodies have also been used to blockade MIF activity as shown in U.S. Pat. No. 6,030,615. MIF expression can also be inhibited using antisense technology as disclosed in U.S. patent application Ser. No. 08/738,947, filed Oct. 24, 1996, now pending, or U.S. Pat. No. 6,268,151 which further demonstrates pharmaceutical formulations that can be used with all the above-mentioned MIF inhibitors.
Lipopolysaccharide (LPS) depresses intrinsic myocardial contractility and is thought to be important in myocardial dysfunction that occurs in sepsis and septic shock (A. M. Lefer, “Mechanisms of cardiodepression in endotoxin shock”, Circ Shock Suppl 1:1-8 (1979), J. E. Parrillo, et al., “A circulating myocardial depressant substance in humans with septic shock. Septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocartdial cell performance”, J. Clin. Invest. 76:1539-1553 (1985), J. M. Reilly, et al., “A circulating myocardial depressant substance is associated with cardiac dysfunction and peripheral hypoperfusion (lactic acidemia) in patients with septic shock”, Chest. 95:1072-1080 (1989)). Many pro-inflammatory cytokines are released after an LPS challenge and have been shown to directly mediate the observed cardiac dysfunction including TNF-α, IL-1β, IL-6, IL-18, NO, and macrophage migration inhibitory factor (MIF) (O. Court, et al., “Clinical review: Myocardial depression sepsis and septic shock”, Crit. Care 6:500-508 (2002), L. B. Gamer, et al., “Macrophage migration inhibitory factor is a caridac-derived myocardial depressant factor”, Am. J. Physiol Heart Circ Physiol, 285:H2500-2509 (2003), S. Krishnagopalan, et al., “Myocardial dysfunction in the patient with sepsis”, Curr. Opin. Crit. Care 8:376-388 (2002)). We recently described macrophage migration inhibitory factor (MIF) as a cardiac derived myocardial depressant factor in a model of sublethal endotoxin challenge (endotoxicosis) (L. B. Gamer, et al., “Macrophage migration inhibitory factor is a cardiac-derived myocardial depressant factor”, Am. J. Physiol Heart Circ. Physiol 285:H2500-2509 (2003)). An LPS challenge induced the constitutive presence of the proinflammatory cytokine MIF to be released maximally by 12 hours. The release of MIF in this model paralleled the cardiac dysfunction that MIF was shown to mediate which was delayed after LPS challenge. Neutralization of MIF by anti-MIF antibodies resulted in significant protection starting at 8 hours and was completed ablated by 48 hours ((L. B. Garner, et al., “Macrophage migration inhibitory factor is a cardiac-derived myocardial depressant factor”, Am. J. Physiol Heart Circ. Physiol 285:H2500-2509 (2003))). MIF is unique among the aforementioned cytokines in its delayed release and ability to block downstream mediators.
Investigators have previously reported a temporal discordance between the TNF-α levels in the myocardium and the contractile dysfunction that occurred during endotoxemia (X. Meng, et al., “TNF-alpha and myocardial depression in endoxtoxemic rats: temporal discordance of an obligatory relationhship”, Am. J. Physiol 275:R502-508 (1998)). That is, cardiac dysfunction did not occur until TNF-α levels had returned to baseline suggesting that TNF-α is an important sentinel signal for other cardiac depressants which more directly conspire to cause dysfunction in sepsis. The significance of these early cytokines is unknown, however therapeutic strategies against early mediators of septic shock such as anti-IL-1β and anti-TNF-α modalities have been tested in human trials, no benefits have been observed likely due to their early appearance in the disease process (C. J. Fisher, et al., “Recombinant human inerleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial”, Phase III rhIL-1ra Sepsis Syndromve Study Group, Jama, 271:1836-1843 (1994), C. J. Fisher, et al., “Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial”, The IL-1RA Sepsis Syndrome Study Group, Crit. Care Med., 22:12-21 (1994), C. Natanson, et al., “Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis”, Ann. Intern. Med., 120:771-783 (1994), K. Reinhart, et al., “Anti-tumor necrosis factor therapy in sepsis:update on clinical trials and lessons learned”, Crit. Care Med., 29:S121-125 (2001)).
Macrophage migration inhibitory factor (MIF) is involved in the pathogenesis of several diseases, including sepsis. MIF opposes the anti-inflammatory effects of glucocorticoids, and also significantly alters tissue metabolism. Although MIF appears to be ubiquitously expressed, there are currently no publications indicating whether MIF is expressed in the myocardium in vivo, or whether release of MIF from the myocardium or other tissues during sepsis could adversely affect cardiac performance.
Cardiac dysfunction during sepsis (O. Court, et al., “Clinical review: Myocardial depression sepsis and septic shock”, Crit. Care, 6:500-508 (2002), S. Krishnagopalan, et al., “Macrophage Dysfunction in the Patient with Sepsis”, Curr. Opin. Crit. Care, 8, 376-388 (2002)) is associated with poor outcome in both humans (P. Ammann, et al., “Elevation of Troponin I in Sepsis and Septic Shock”, Intensive Care Med., 27, 965-969 (2001), C. N. Sessler, et al., “New Concepts in Sepsis”, Curr. Opin. Crit. Care, 8, 465-472 (2002)) and animal models (M. Bozza, et al., “Targeted Disruption of Migration Inhibitory Factor Gene Reveals Its Critical Role in Sepsis”, J. Exp. Med., 189, 341-346 (1999), T. Calandra, et al., “Protection from Septic Shock by Neutralization of Macrophage Migration Inhibitory Factor”, Nat. Med., 6, 164-170 (2000)). It has been previously demonstrated that sepsis or burn associated cardiac dysfunction is primarily due to circulating myocardial depressant factors, including TNF-α (B. P. Giroir, et al., “Inhibition of Tumor Necrosis Factor Prevents Myocardial Dysfunction During Burn Shock”, Am. J. Physiol., 267, H118-H124 (1994), Haudek, et al., “Differential Regulation of Myocardial NF Kappa B Following Acute or Chronic TNF-Alpha Exposure”, J. Mol. Cell. Cardiol., 33, 1263-1271 (2001), A. Kumar, et al., “Tumor Necrosis Factor Alpha and Interleukin 1 Beta are Responsible for in vitro Myocardial Cell Depression Induced by Human Septic Shock Serum”, J. Exp. Med., 183, 949-958 (1996)). However, since TNF-α is a sentinel, rapid response cytokine, and is gone from the circulation days or weeks before the resolution of myocardial dysfunction, there remains a need for finding whether additional myocardial depressant proteins might exist.
Studies utilizing live bacteria, either by direct injection of E coli i.p. or by cecal ligation and puncture (CLP), have previously demonstrated that MIF plasma and/or peritoneal fluid levels increase several hours post challenge, and that antibodies against MIF protected the mice from lethal bacterial peritonitis (T. Calandra, et al., “Protection from septic shock by neutralization of macrophage migration inhibitory factor”, Nat. Med., 6, 164-170 (2000)). Moreover, mice were protected when the antibodies were given as late as 8 h after the onset of infection (T. Calandra, et al., “Protection from septic shock by neutralization of macrophage migration inhibitory factor”, Nat. Med., 6, 164-170 (2000)).
MIF has a number of properties that make it unique among cytokines. MIF is released preformed from numerous cell types including lymphocytes, macrophages, and the anterior pituitary (J. Bernhagen, et al., “Regulation of the Immune Response by Macrophage Migration Inhibitory Factor: Biological and Structural Features”, J. Mol. Med., 76, 151-161 (1998), T. Calandra, et al., “Macrophage Migration Inhibitory Factor (MIF): A Glucocorticoid Counter-Regulator Within the Immune System”, Crit. Rev. Immunol., 17, 77-88 (1997), S. C. Donnelly, et al., “Macrophage Migration Inhibitory Factor: A Regulator of Glucocorticoid Activity with a Critical Role in Inflammatory Disease”, Mol. Med. Today, 3, 502-507 (1997), R. A. Mitchell, et al., “Tumor Growth-Promoting Properties of Macrophage Migration Inhibitory Factor (MIF)”, Semin. Cancer Biol., 10, 359-366 (2000)). However, the list of sources of MIF continues to grow and includes other tissues such as lung, liver, adrenal, spleen, kidney, skin, muscle, thymus, skin, and testes (M. Bacher, et al., “Migration Inhibitory Factor Expression in Experimentally Induced Endotoxemia”, Am. J. Pathol., 150, 235-246 (1997), G. Fingerle-Rowson, et al., “Regulation of Macrophage Migration Inhibitory Factor Expression by Glucocorticoids in vivo”, Am. J. Pathol, 162, 47-56 (2003)). MIF has at least 2 catalytic activities that are distinct: tautomerase and oxidoreductase activity. To this end, pharmacological inhibitors of MIF tautomerase activity have been developed for the treatment of MIF-related diseases such as sepsis, acute respiratory distress syndrome (ARDS), asthma, atopic dermatitis, rheumatoid arthritis, nephropathy, and cancer (A. Dios, et al., “Inhibition of MIF Bioactivity by Rational Design of Pharmacological Inhibitors of MIF Tautomerase Activity”, J. Med. Chem., 45, 2410-2416 (2002), M. Orita, et al., “Macrophage Migration Inhibitory Factor and the Discovery of Tautomerase Inhibitors”, Curr. Pharm. Des., 8, 1297-1317 (2002)). These diseases have shown benefit from anti-MIF antibodies.
Several investigations indicate that MIF may exert effects by both direct and indirect mechanisms. Previous studies have provided evidence that MIF promotes the release and pharmacodynamic effects of other pro-inflammatory cytokines. Macrophages expressing anti-sense MIF cDNA (leading to less endogenous MIF) secrete/express significantly less TNF-α, IL-6, and NO, while NF-κB activity is decreased in response to LPS (44). Therefore, it appears that MIF may directly interact with the LPS signaling pathway (H. Lue, et al., “Macrophage Migration Inhibitory Factor (MIF): Mechanisms of Action and Role in Disease”, Microbes Infect., 4, 449-460 (2002)). Moreover, MIF knockout (MIFKO) mice, as demonstrated in U.S. patent application Ser. No. 10/322,685 filed Dec. 19, 2002, which are resistant to lethal doses of LPS, have lower circulating plasma levels of TNF-α compared to wild-type mice at baseline. Upon LPS challenge, they demonstrate diminished circulating TNF-α concentrations, increased nitric oxide (NO) concentrations, and unchanged IL-6 and IL-12 concentrations (M. Bozza, et al., “Targeted Disruption of Migration Inhibitory Factor Gene Reveals Its Critical Role in Sepsis”, J. Exp. Med. 189, 341-346 (1999)). While MIF appears to promote pro-inflammatory cytokines, the effects of MIF have been shown to act in a TNF-α-independent manner. When CLP was performed in TNF-α knock out mice, a 60% survival rate was seen in mice administered anti-MIF antibodies compared to a 0% survival rate in wild-type mice (T. Calandra, et al., “Protection from Septic Shock by Neutralization of Macrophage Migration Inhibitory Factor”, Nat. Med., 6, 164-170 (2000)).
In relation to cardiac dysfunction not related to sepsis, elevated serum MIF concentrations have also been described in patients following acute myocardial infarction (M. Takahashi, et al., “Elevation of Plasma Levels of Macrophage Migration Inhibitory Factor in Patients with Acute Myocardial Infarction”, Am. J. Cardiol., 89, 248-249 (2002), M. Takahashi, et al., “Macrophage Migration Inhibitory Factor as a Redox-Sensitive Cytokine in Cardiac Myocytes”, Cardiovasc Res., 52, 438-445 (2001), C. M. Yu, et al., “Elevation of Plasma Level of Macrophage Migration Inhibitory Factor in Patients with Acute Myocardial Infarction”, Am. J. Cardiol., 88, 774-777 (2001)), with heretofore unknown physiologic relevance. Similarly, cultured cardiac myocytes have been noted to release MIF in response to hypoxia and hydrogen peroxide (free radical initiator) but not angiotensin II, endothelin-1, IL-1β, or TNF-α (J. Fukuzawa, et al., “Contribution of Macrophage Inhibitory Factor to Extracellular Signal-Regulated Kinase Activation by Oxidative Stress in Cardiomyocytes”, J. Biol. Chem., 277, 24889-24895, M. Takahashi, et al., “Macrophage Migration Inhibitory Factor as a Redox-Sensitive Cytokine in Cardiac Myocytes”, Cardiovasc Res., 52, 438-445 (2001)). There are many clinical scenarios which could potentially trigger myocardial MIF release, thereby adversely affecting cardiac function. Cardiac dysfunction can be manifest through any irregular condition in the cardiac myocytes and cardiac tissue. Such dysfunctions include, but are not limited to, mycarditis, endocarditis, pericarditis, rheumatic heart disease, myocardial infarction, arrythmia, fibrillation, cardiogenic shock, ischemia, hypertrophy, cardiomyopathy, angina, heart murmur or palpitation, heart attack or failure, and any of the symptoms or defects associated with congenital heart diseases generally.
Macrophage migration inhibitory factor is a expressed in many organs including the heart and has been linked with a delayed cardiac dysfunction in a murine model of endotoxicosis (Garner, et al., “Macrophage Migration Inhibitory Factor is A Cardiac-Derived Myocardial Depressant Factor”, Am. J. Physiol. Heart Circ. Physiol, 258, H2500-H2509 (2003)).
Burn injury results in cardiac injury and contractile dysfunction involving decreased cardiac output, shock, and left ventricular failure (J. T. Murphy, et al., “Evaluation of Troponin-I as An Indicator of Cardiac Dysfunction After Thermal Injury, 45, 700-704, (1998), E. M. Reynolds, et al., “Left Ventricular Failure Complicating Severe Pediatric Burn Injuries”, J. Pediatr. Surg. 30, 264-269; discussion 269-270 (1995), W. C. Shoemaker, et al., ”Burn Pathophysiology In Man. I. Sequential Hemodynamic Alterations, J. Surg. Res., 14, 64-73 (1973), R. R. Wolfe, et al., “Review: Acute Versus Chronic Response to Burn Injury”, Circ. Shock, 8, 105-115 (1981)). These contractile deficits have been reported to appear as early as 2 hours after burn injury (J. W. Horton, et al., “Postburn Cardiac Contractile Function and Biochemical Markers of Postburn Cardiac Injury”, J. Am. Coll. Surg., 181, 289-298 (1995)). Several recent studies have elucidated the early molecular events which involve an endotoxin signaling pathway including the toll-like receptor 4 (Tlr-4), IRAK, and NF-kB in response to gut derived factors (D. L. Carlson, et al., “I Kappa B Overexpression in Cardiomyocytes Prevents NF-Kappa B Translocation and Provides Cardioprotection in Trauma”, Am. J. Physiol. Heart Circ. Physiol, 284, H804-814 (2003), J. T. Sambol, et al., “Burn-Induced Impairment of Cardiac Contractile Function is Due to Gut-Derived Factors Transported in Mesenteric Lymph”, Shock, 18, 272-276 (2002), J. A. Thomas, et al., “IRAK Contributes to Burn-Triggered Myocardial Contractile Dysfunction”, Am. J. Physiol. Heart Circ. Physiol., 283, H829-836 (2002), J. A. Thomas, et al., “TLR4 Inactivation and rBPI(21) Block Burn-Induced Myocardial Contractile Dysfunction”, Am. J. Physiol. Heart Circ. Physiol., 283, H1645-1655 (2002)).
While endotoxin signaling through the Tlr-4 receptor represents the initial pathway of burn injury associated cardiac dysfunction, other investigators have demonstrated that early downstream mediators include TNF-α, IL-1β, and IL-6 (H. Lue, et al., “Macrophage Migration Inhibitory Factor (MIF): Mechanisms of Action and Role in Disease”, Microbes Infect., 4, 449-460 (2002)). Experimentally, when TNF-α is blocked, burn injury associated cardiac dysfunction is decreased, emphasizing its importance as a key regulator of dysfunction (B. P. Giroir, et al., “Inhibition of Tumor Necrosis Factor Prevents Myocardial Dysfunctional During Burn Shock”, Am. J. Physiol., 267, H118-124 (1994)). When therapeutic strategies against early mediators of septic shock such as anti-IL-1β and anti-TNF-α modalities have been tested in human trials, no benefits have been observed likely due to their early appearance in the disease process (C. J. Fisher Jr., et al., “Recombinant Human Interleukin 1 Receptor Antagonist in the Treatment of patients with Sepsis Syndrome, Results from a Randomized, Double-Blind, Placebo-Controlled Trial”, Phase III rhIL-1ra Sepsis Syndrome Study Group, Jama. 271, 1836-1843 (1994), C. J. Fisher, et al., “Initial Evaluation of Human Recombinant Interleukin-1 Receptor Antagonist in the Treatment of Sepsis Syndrome: A Randomized, Open-Label, Placebo-Controlled Multicenter Trial”, The IL-1RA Sepsis Syndrome Study Group, Crit. Care Med., 22, 12-21 (1994), C. Natanson, et al., “Selected Treatment Strategies for Septic Shock Based on Proposed Mechanisms of Pathogenesis”, Ann. Intern. Med., 120, 771-783 (1994), K. Reinhart, et al., “Anti-Tumor Necrosis Factor Thereapy in Sepsis: Update on Clinical Trails and Lessons Learned”, Crit. Care Med., 29, S121-125 (2001)).
Recently, the cytokine known as macrophage migration inhibitory factor (MIF) has been shown to play a key role in sepsis mortality (H. Lue, et al., “Macrophage Migration Inhibitory Factor (MIF): Mechanisms of Action and Role in Disease”, Micorbes Infect., 4, 449-460 (2002)). In fact, anti-MIF therapy has been shown to improve survival significantly in lethal models of sepsis (cecal ligation and puncture), even when given up to 8 hours after the insult (T. Calandra, et al., “Protection From Septic Shock Byneutralization of Macrophage Migration Inhibitory Factor”, Nat. Med., 6, 164-170 (2000)). Moreover, MIF has been shown to play a key role in ARDS (K. N. Lai, et al., “Role For Macrophage Migration Inhibitory Factor in Acute Respiratory Distress Syndrome”, J. Pathol., 199, 496-508 (2003)), a common complication of burn injury (M. Bhatia, et al., “Role of Inflammatory Mediators in the Pathophysiology of Acute Respiratory Distress Syndrome”, J. Pathol., 202, 145-156 (2004)). The purpose of this study was then to identify and characterize MIF as a useful therapeutic target of burn injury associated cardiac morbidity using a well defined murine model of burn injury (Garner, et al., “Macrophage Migration Inhibitory Factor is a Cardiac-Derived Myocardial Depressant Factor”, Am. J. Physiol. Heart Circ. Physiol., 285, H2500-2509 (2003)).
Accordingly, there remains a need for therapies for cardiodepression, cardiodysfunction, burn associated morbidities and cardioprotection in which no therapy is currently available.
U.S. Pat. No. 6,030,615 relates to methods and compositions for treating a disease caused by cytokine-mediated toxicity.
U.S. Pat. No. 6,420,188 relates to methods and compositions for antagonizing MIF activity and methods of treating various diseases based on this activity.
U.S. Pat. No. 6,599,938 relates to methods and compositions for antagonizing MIF activity and methods of treating various diseases based on this activity.
U.S. Pat. No. 6,645,493 relates to compositions and methods for inhibiting the release and/or biological activity of MIF.